This invention is concerned with a drug bioaffecting, body-treating process which employs the pyrimidine compound 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl]-8-azaspiro[4.5]decane-7,9-di one or a pharmaceutically acceptable acid addition salt thereof (class 424, subclass 251).
This pyrimidine compound with which the present invention is concerned has the following structural formula ##STR1## and is known as buspirone. The hydrochloride salt has been referred to in the prior art as MJ 9022-1 and as buspirone hydrochloride. Other acid addition salts thereof are named by combining "buspirone" with the appropriate word to define the acid from which it is prepared as in "buspirone hydrochloride". The latter is the United States Adopted Name (USAN); refer to J. American Med. Assoc. 225, 520 (1973).
The synthesis of the compound and the disclosure of its psychotropic properties are described in the following patents and publications.
1. Y. H. Wu, et al., J. Med. Chem., 15, 477 (1972). PA0 2. Y. H. Wu, et al., U.S. Pat. No. 3,717,634 which issued Feb. 20, 1973. PA0 3. L. E. Allen, et al., Arzneim. Forsch., 24, PA0 4. G. L. Sathananthan, et al., Current Therapeutic Research, 18/5, 701-705 (1975). PA0 5. Y. H. Wu, et al., U.S. Pat. No. 3,976,776, issued August 24, 1976.
No. 6, 917-922 (1974).
The use of buspirone hydrochloride as a novel anti-anxiety agent for the treatment of neurotic patients is described in G. P. Casten, et al., U.S. Pat. No. 4,182,763, issued Jan. 9, 1980. A New Drug Application (NDA) has been approved by the U.S. Food & Drug Administration for the use of buspirone in the treatment of general anxiety disorder.
Buspirone has also been disclosed as being useful in the treatment of other disorders. Allen, et al., U.S. Pat. No. 4,438,119, issued Mar. 20, 1984, disclosed buspirone's use in alleviation of extrapyramidal motor disorders.
Currently, other clinical studies are being conducted to provide support for the use of buspirone in panic disorders and in the treatment of sexual dysfunction. The use of buspirone for alleviation of panic disorders has been disclosed in U.S. Ser. No. 791,182, which is currently pending; and buspirone's use in treating sexual dysfunction has been disclosed in U.S. Ser. No. 825,826, also currently pending
The present invention can be distinguished from the above prior art in that it is directed to a use which is unexpected and which can be distinguished from its application in the above-described disorders. Usefulness in any or all of these clinical disorders would not suggest or in any way make obvious the use of buspirone in short-term memory improvement.
Other drugs have been reported to be useful in memory enhancement although there is no drug which is presently accepted as a standard for this use. The general area is further complicated as to applicability of improvement, i.e. whether any improvement represents a normalization of cognitive function in an impaired population, above normal enhanced performance in an unimpaired population, or an improvement in memory regardless of degree of impairment. In any event, pharmacological agents have been reported to result in cognitive improvement in various populations of people who have been treated. Some examples of these populations are geriatric subjects, patients with Alzheimer's disease, demented patients, cognitively impaired patients, anxious patients, and normal subjects. Substances used in these studies have comprised cholinergic pre-synaptic agents such as choline, piracetam, 4-aminopyridine, and lecithin; synaptic agents such as physostigmine; and post-synaptic agents such as arecholine. Miscellaneous agents such as vasopressin, and naloxone; and vasodilators such as cyclospasmol and hydergine have also been reported. None of these substances would suggest the use of buspirone for improvement of memory.
The following specific references may be considered to be representative of the prior art concerning reports of memory enhancement by pharmacologic agents.
Friedman, et al., New England Journal of Medicine, 304;1490-1491 (1981) reported a study in ten patients with mild to moderate memory impairment which were treated with choline and piracetam for seven days. A mean improvement of 70% in verbal memory retrieval was obtained.
Wesseling, et al., New England Journal of Medicine, 310:985-989 (1984) reported a study in 14 patients with Alzheimer's disease who were given 4-aminopyridine for 12 weeks in a double-blind, randomized, cross-over study. Treatment with 4-aminopyridine resulted in significant improvement in recent-memory testing for patients.
Davis, et al., American Journal of Psychiatry, 139:1421-1424 (1981) reported improvement in recognition memory testing for 10 Alzheimer's disease patients who received physostigmine. In normal subjects, however, Davis, et al., Science, 201:272-274 (1978) reported that physostigmine significantly enhanced long-term memory processes but not short-term memory processes.
Sitaram, et al., Science, 201:274-276 (1978) reported that arecholine significantly enhanced serial learning in normal human subjects.
Shader, et al., Journal American Geriatric Society, 22:107-113 (1974) reported that hydergine-treated patients showed a small but significant improvement in recent memory.
In summary, there exists nothing in the prior art that would teach or suggest that buspirone and its pharmaceutically acceptable salts would be useful in improving short-term memory.